Aims: Advanced age is associated with an increased risk of adverse cardiovascular events. The relationship between biological age acceleration (BAA), cardiac size, cardiac function, and heart failure (HF) is not well-defined. Methods and results: Utilizing the UK Biobank cohort, we assessed biological age using the Klemera–Doubal and PhenoAge methods. BAA was quantified by residual analysis compared with chronological age. Cardiovascular magnetic resonance (CMR) imaging provided detailed insights into cardiac structure and function. We employed multivariate regression to examine links between BAA and CMR-derived cardiac phenotypes. Cox proportional hazard regression models analysis was applied to explore the causative relationship between BAA and HF. Additionally, Mendelian randomization was used to investigate the genetic underpinnings of these associations. A significant correlation was found between increased BAA and deleterious changes in cardiac structure, such as diminished left ventricular mass, lower overall ventricular volume, and reduced stroke volumes across ventricles and atria. Throughout a median follow-up of 13.8 years, participants with greater biological aging showed a heightened risk of HF [26% per standard deviation (SD) increase in KDM-BA acceleration, 95% confidence intervals (CI): 23–28%; 33% per SD increase in PhenoAge acceleration, 95% CI: 32–35%]. Mendelian randomization analysis suggests a likely causal link between BAA, vital cardiac metrics, and HF risk. Conclusion: In this cohort, accelerated biological aging may serve as a risk indicator for altered cardiac dimensions, functionality, and the onset of heart failure among middle-aged and elderly adults. It holds promise as a focal point for evaluating risk and developing targeted interventions.

Background: Accumulating evidence suggests that regulated cell death, such as pyroptosis, apoptosis, and necroptosis, is deeply involved in the pathogenesis of psoriasis. As a newly recognized form of systematic cell death, PANoptosis is involved in a variety of inflammatory disorders through amplifying inflammatory and immune cascades, but its role in psoriasis remains elusive. Objectives: To reveal the role of PANoptosis in psoriasis for a potential therapeutic strategy. Methods: Multitranscriptomic analysis and experimental validation were used to identify PANoptosis signaling in psoriasis. RNA-seq and scRNA-seq analyses were performed to establish a PANoptosis-mediated immune response in psoriasis, which revealed hub genes through WGCNA and predicted disulfiram as a potential drug. The effect and mechanism of disulfiram were verified in imiquimod (IMQ)-induced psoriasis. Results: Here, we found a highlighted PANoptosis signature in psoriasis patients through multitranscriptomic analysis and experimental validation. Based on this, two distinct PANoptosis patterns (non/high) were identified, which were the options for clinical classification. The high-PANoptosis-related group had a higher response rate to immune cell infiltration (such as M1 macrophages and keratinocytes). Subsequently, WGCNA showed the hub genes (e.g., S100A12 , CYCS , NOD2 , STAT1 , HSPA4 , AIM2 , MAPK7 ), which were significantly associated with clinical phenotype, PANoptosis signature, and identified immune response in psoriasis. Finally, we explored disulfiram (DSF) as a candidate drug for psoriasis through network pharmacology, which ameliorated IMQ-mediated psoriatic symptoms through antipyroptosis-mediated inflammation and enhanced apoptotic progression. By analyzing the specific ligand—receptor interaction pairs within and between cell lineages, we speculated that DSF might exert its effects by targeting keratinocytes directly or targeting M1 macrophages to downregulate the proliferation of keratinocytes. Conclusions: PANoptosis with its mediated immune cell infiltration provides a roadmap for research on the pathogenesis and therapeutic strategies of psoriasis.

Immunotherapy is a vital treatment for patients with cutaneous melanoma (CM), but effective predictors to guide clinical immunotherapy are lacking. Cuproptosis is a newly discovered mode of cell death related to tumorigenesis. Exploring the relationship between the mode of cuproptosis and the effect of immunotherapy on CM could better guide clinical management. We clustered all patients with CM in the Cancer Genome Atlas (TCGA) database based on cuproptosis-related genes (CRGs). Prognosis, immunotherapeutic effect, tumor microenvironment score, expression of CD274, CTLA4, and PDCD1, and abundance of CD8 + T infiltration in group A were higher than in group B. Using a combination of LASSO and COX regression analysis, we identified 10 molecules significant to prognosis from differentially expressed genes between the two groups and constructed a cuproptosis-related scoring system (CRSS). Compared with the American Joint Committee on Cancer (AJCC) staging system, CRSS more accurately stratified CM patient risk and guided immunotherapy. CRSS successfully stratified risk and predicted the effect of immunotherapy in 869 patients with eight CM immunotherapy datasets and multiple other tumor immunotherapy cohorts. The nomogram model, which combined AJCC stage and CRSS, greatly improved the ability and accuracy of prognosis prediction. In general, our cuproptosis-related scoring system and nomogram model accurately stratified risk in CM patients and effectively predicted prognosis and the effect of immunotherapy in CM patients.

Rosacea is a chronic skin disorder characterized by abnormal neurovascular and inflammatory conditions on the central face. Despite increasing evidence suggesting that rosacea is associated with metabolic disorders, the role of metabolism in rosacea pathogenesis remains unknown. Here, via a targeted metabolomics approach, we characterized significantly altered metabolic signatures in patients with rosacea, especially for amino acid-related metabolic pathways. Among these, glutamic acid and aspartic acid were highlighted and positively correlated with the disease severity in patients with rosacea. We further demonstrated that glutamic acid and aspartic acid can facilitate the development of erythema and telangiectasia, typical features of rosacea, in the skin of mice. Mechanistically, glutamic acid and aspartic acid stimulated the production of vasodilation-related neuropeptides from peripheral neurons and keratinocytes and induced the release of nitric oxide from endothelial cells and keratinocytes. Interestingly, we provided evidence showing that doxycycline can improve the symptoms of patients with rosacea possibly by targeting the amino acid metabolic pathway. These findings reveal that abnormal amino acid metabolism promotes neurovascular reactivity in rosacea and raise the possibility of targeting dysregulated metabolism as a promising strategy for clinical treatment.

Emerging evidence suggests that long noncoding RNAs (lncRNAs) play essential roles in the regulation of gene expression. However, the functional contributions of lncRNAs to adipogenesis remain largely unexplored. In this study, we investigated global changes in the expression patterns of lncRNAs in visceral adipose tissue and identified RP11-142A22.4 as a significantly upregulated lncRNA. In isolated preadipocytes, knockdown of RP11-142A22.4 inhibited differentiation and reduced C/EBP-α and PPAR-γ expression. Investigations of the underlying mechanisms revealed that RP11-142A22.4 contains a functional miR-587 binding site. Mutation of the binding sites for RP11-142A22.4 in miR-587 abolished the interaction, as indicated by a luciferase reporter assay. Furthermore, RP11-142A22.4 affected the expression of miR-587 and its target gene Wnt5β. Overexpression of miR-587 blocked the inhibitory effect of RP11-142A22.4 on preadipocyte differentiation. Moreover, the downregulation of miR-587 restored preadipocyte differentiation upon inhibition by RP11-142A22.4 silencing. Our results suggest that RP11-142A22.4 can control adipocyte differentiation via the miR-587/Wnt5β signaling pathway and serve as a potential target for obesity treatments.

Background and objective: Existing cross-sectional and retrospective studies were unable to establish a causal relationship between psoriasis and cutaneous melanoma (CM). We sought to evaluate the causal role between psoriasis and CM.Methods: We performed a bidirectional two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of psoriasis and CM among individuals of predominantly European ancestry. Mendelian randomization–Egger regression, inverse variance weighting, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, weighted mode, and weighted median were used to examine the causal effect between psoriasis and CM.Results: Genetically predicted psoriasis was a significant risk factor for CM (odds ratio, 1.69; 95% confidence interval, 1.15–2.48; P = 0.025). In contrast, no association was observed between genetically predicted CM and psoriasis.Conclusion: Our findings corroborated the existence of genetically predicted psoriasis increases risk of CM. Enhanced early screening of cutaneous melanoma in patients with psoriasis may improve clinical burden. However, we did not find evidence for a causal link from CM to psoriasis, so further studies are required to elucidate the effect of CM activity on psoriasis.